CN106750250A - Using amino acid as polyethylene glycol oleanolic acid derivate of linking arm and its preparation method and application - Google Patents
Using amino acid as polyethylene glycol oleanolic acid derivate of linking arm and its preparation method and application Download PDFInfo
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- CN106750250A CN106750250A CN201611189746.7A CN201611189746A CN106750250A CN 106750250 A CN106750250 A CN 106750250A CN 201611189746 A CN201611189746 A CN 201611189746A CN 106750250 A CN106750250 A CN 106750250A
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic
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Abstract
Using amino acid as polyethylene glycol oleanolic acid derivate of linking arm and its preparation method and application, it is related to a kind of derivative and its preparation method and application, its general structure is：Wherein, X=Y=CH2Or X=H, Y=0, R represent H, CH3, CH (CH3)2, CH2CH(CH3)2, CHCH3(CH2CH3), CH2C6H5, (CH2)2‑S‑CH3；The C3 hydroxyl the present invention relates to polyethylene glycol to be connected to oleanolic acid by amino acid as linking arm, is prepared for a series of oleanolic acid derivates, substantially increases the water solubility of oleanolic acid.Further pharmacology activity research shows that such compound is significantly better than oleanolic acid at aspects such as antitumor activities.Oleanolic acid derivate of the invention and pharmaceutical composition are expected to develop anti-cancer agent.
Description
Technical field
The present invention relates to a kind of medicine group biology and its preparation method and application, it is more particularly to a kind of using amino acid as
Polyethylene glycol oleanolic acid derivate of linking arm and its preparation method and application.
Background technology
Recently there is document report polyethylene glycol（PEG）The method of modification can be used for Chinese medicine hardly soluble active ingredient prodrug
Synthesis.PEG often combines that water is insoluble or water as a kind of nontoxic, good biocompatibility, the pharmaceutical carrier without infection and nonantigenic
The low molecule of dissolubility plays the effect of its solubilising.Amino acid has good biocompatibility and compatibility, and cheap and easy to get,
Field of medicaments plays very important effect, and partial antitumor medicine increased the target to tumour cell after amino acid modified
Tropism, antitumor activity is significantly improved, and the toxic action to organism normal cell also decreases.
Oleanolic acid（Oleanolic Acid, OA, Fig1）As the Typical Representative of pentacyclic triterpenoid, with aobvious
The pharmacological activity such as the antitumor of work, anti-inflammatory, anti-oxidant, platelet aggregation-against.But oleanolic acid is water-soluble excessively poor, limits
Its clinical practice.To increase its dissolubility and bioavilability, the method that PEG is modified introduces the synthesis of oleanolic acid prodrug
In, use a series of PEG of different relative molecular masses to be used as linking arm by different aminoacids and synthesized oleanolic acid and spread out
It is biological.By the structure of modification to oleanolic acid, water-soluble and extension Half-life in vivo is improved, improve its bioactivity, be expected to
Medicine of the exploitation with applications well prospect.
The content of the invention
It is an object of the invention to provide one kind,.
The purpose of the present invention is achieved through the following technical solutions：
A kind of polyethylene glycol oleanolic acid derivate using amino acid as linking arm, its general structure is：
Wherein, X=Y=-CH2Or X=H, Y=0, R represent-H ,-CH3,-CH (CH3)2,-CH2CH(CH3)2,-CHCH3(CH2CH3) ,-
CH2C6H5,-(CH2)2-S-CH3；MPEG selects mPEG1000, mPEG2000, mPEG5000, mPEG6000, mPEG8000, mPEG10000,
mPEG20000。
A kind of polyethylene glycol oleanolic acid derivate preparation method using amino acid as linking arm, the derivative by with
It is prepared by lower step：
（1）MPEG is dissolved in anhydrous propanone, lower dropwise addition triethylamine is stirred at room temperature, the tolysulfonyl in anhydrous propanone will be dissolved in
Chlorine, in dropping to above-mentioned solution, stirring reaction at 0-40 DEG C；After reaction terminates, suction filtration removes triethylamine hydrochloride precipitation；Filtrate
It is added dropwise to after concentration in cooling absolute ether, separates out solid, absolute ethyl alcohol recrystallization obtains white solid mPEG-OTs；
（2）MPEG-OTs is dissolved in DMF, the sodium salt or sylvite of amino acid is added, in stirring reaction at 40-90 DEG C；Reaction
After end, insoluble matter is filtered to remove, filtrate is added dropwise in cooling absolute ether under stirring, precipitation, ether is collected by filtration
Cleaning, vacuum drying.Solid is dissolved in distilled water, pH to 3, CH is adjusted with hydrochloric acid2Cl2Extraction 3 times, combining extraction liquid, washing,
Anhydrous Na2SO4It is dried overnight, solution decompression is steamed to 1/10th of original volume after filtering, is added drop-wise in cooling absolute ether, obtains
White precipitate, vacuum drying, obtains white solid mPEG- amino acid derivativges；
（3）MPEG- amino acid and oleanolic acid are dissolved in dry dichloromethane, are stirred in ice-water bath, add 4- diformazan ammonia
Yl pyridines（DMAP）And N, N- dicyclohexylcarbodiimide（DCC）, room temperature reaction；Filter after completion of the reaction, wash organic phase, nothing
Water Na2SO4Dry, filtering, concentrate and precipitated with absolute ether, suction filtration, vacuum drying obtains target compound.
Using amino acid as the application of the polyethylene glycol oleanolic acid derivate of linking arm, the oleanolic acid derivate
Pharmaceutical composition has antitumor activity, for treating tumor disease.
Advantages of the present invention is with effect：
The water-soluble and active compound oleanolic acid contrast of the mPEG-AA-OA compounds that the present invention is provided, at least improves 1000 times,
It can be seen that PEGylation has obvious solubilizing effect.
The mPEG-AA-OA compounds that the present invention is provided are suppressed three between superoxide anion and 1,1- diphenyl -2- by external
Nitrophenyl hydrazine（DPPH）Active testing.Result shows that such compound has good antioxidation activity.
The mPEG-AA-OA compounds that the present invention is provided carry out preliminary anti tumor activity in vitro and test using mtt assay.Grind
Study carefully result to show, synthesized part of compounds has various tumor cell strains obvious inhibitory action, as a result better than neat pier
Tartaric acid.
Specific embodiment
With reference to embodiment, the present invention is described in detail.
Embodiment 1：mPEG5000The preparation of-OTs
By 5. 0 g mPEG5000It is dissolved in 50mL anhydrous propanones, lower dropwise addition triethylamine 2mL (14. 4mmol) is stirred at room temperature,
The paratoluensulfonyl chloride 2g (6. 4mmol) that will be dissolved in 5 mL anhydrous propanones is dropped in above-mentioned solution, room temperature reaction mistake
Night.Reaction is filtered to remove triethylamine hydrochloride precipitation after terminating.It is added dropwise over after concentrate the filtrate to original solution 1/10th
Into cooling absolute ether 200 mL, solid is separated out, precipitation is collected by filtration, be vacuum dried, absolute ethyl alcohol recrystallization obtains white solid
Body mPEG5000- OTs (4. 24 g, 85%).
Other molecular weight mPEG can be obtained with method5000- OTs compounds.
Embodiment 2：mPEG5000The preparation of-Pro
Take mPEG5000The g of-OTs 2. 0 are dissolved in the mL of DMF 20, add the g of sylvite 0. 38 of proline（2mmol）, return
12 h of stream reaction.Reaction is filtered to remove insoluble matter after terminating, and filtrate is added dropwise into cooling absolute ether 200 mL under stirring
In, precipitation is collected by filtration, ether is cleaned 3 times, and vacuum drying is re-dissolved in the mL of distilled water 50, and 5mol/L hydrochloric acid adjusts pH extremely
3, CH2Cl2Extraction（10mL×3）, combining extraction liquid, washing, then use anhydrous Na2SO4It is dried overnight, solution decompression steams after filtering
To 1/10th of original solution, it is added drop-wise in cooling absolute ether 100 mL, obtains white precipitate, be vacuum dried, obtains white solid
Body（1. 15 g, 58. 0%）；mp:56. 5~60. 5 DEG C；IR（KBr,ν）:3450,2890,1734,1465,1285,
1118,850cm-1。
Different mPEG- amino acid complexes can be obtained with method.
Embodiment 3：mPEG5000The preparation of-Pro-OA
By mPEG5000The g of-the Pro 0. 4 and g of oleanolic acid 0. 053（0. 117 mmol）It is dissolved in dry dichloromethane 20
In mL, stirred in ice-water bath, add DMAP（DMAP）20 mg and N, N- dicyclohexylcarbodiimide（DCC）30
Mg, the h of room temperature reaction 24.Filter after completion of the reaction, wash organic phase twice, anhydrous Na2SO4Dry, filtering is concentrated and with anhydrous
Ether is precipitated, and is vacuum dried after collection, obtains white solid thing mPEG-Pro-OA（0. 38 g, 75%）.mp：56. 5~59.
6℃；IR（KBr,ν）:3384,1732,1640,1400,1106 cm-1。1H NMR (600 MHz, CDCl3) δ(ppm):
5.39 (1H,t, J = 3.4 Hz, H-12), 4.48 (1H,dd, J = 10.0, 5.9 Hz, H-3), 2.56 (1H,
dd, J = 12.8, 3.3 Hz, H-18), 2.05 (3H,s,3-COCH3), 1.16(3H,s,-CH3), 0.93(3H,s,-
CH3), 0.91(6H,s,2CH3), 0.87(3H,s,-CH3), 0.85(3H,s,-CH3), 0.78(3H,s,-CH3), 3. 64
(446H,m,-OCH2CH2-,mPEG-backbone), 6.95( 1H,d,NH).
The mPEG-AA-OA compounds of different molecular weight polyethylene glycol and several amino acids as linking arm can be obtained with method.
Embodiment 4：Solubility test is carried out to mPEG-AA-OA compounds prepared by the present invention.
Respectively by excessive oleanolic acid, mPEG-AA-OA compounds are added in the water of 10mL, these suspensions are put
In 25oShaking 24h in C constant temperature oscillators, 2h is placed after stopping shaking, after reaching balance, is taken supernatant and is filtered with 0.45 μm of micropore
Membrane filtration, takes filtrate, and with high effective liquid chromatography for measuring concentration and their solubility in water are calculated after appropriate dilution.Neat pier
The solubility of tartaric acid and part mPEG-AA-OA conjugates is listed in Table 1 below.MPEG-AA-OA conjugates as shown in table 1 can be notable
Solubility of the oleanolic acid in water is improved, solubility is reduced with the increase of mPEG molecular weight, but is above oleanolic acid.
Embodiment 5：Antitumor activity test has been carried out respectively to mPEG-AA-OA compounds prepared by the present invention.
Preliminary anti tumor activity in vitro is carried out to oleanolic acid and synthesized derivative using mtt assay to test.Part
MPEG-AA-OA derivatives are as shown in table 1 to HepG2 cells in vitro cytotoxicity test results.Result of study shows, synthesized
Part of compounds has obvious inhibitory action to HepG2 tumor cell lines, as a result better than oleanolic acid.
The mPEG-AA-OA compounds dissolubility of table 1 and HepG2 cytotoxic activities
aCompound concentration is 10-5The inhibiting rate measured during mol/L.
Claims (4)
1. a kind of polyethylene glycol oleanolic acid derivate using amino acid as linking arm, it is characterised in that its general structure is：
Wherein, X=Y=-CH2Or X=H, Y=0, R represent-H ,-CH3,-CH
(CH3)2,-CH2CH(CH3)2,-CHCH3(CH2CH3) ,-CH2C6H5,-(CH2)2-S-CH3；MPEG selects mPEG1000, mPEG2000,
mPEG5000, mPEG6000, mPEG8000, mPEG10000, mPEG20000。
2. a kind of polyethylene glycol oleanolic acid derivate preparation method using amino acid as linking arm, it is characterised in that described
Derivative is prepared by following steps：
MPEG is dissolved in anhydrous propanone, lower dropwise addition triethylamine is stirred at room temperature, the paratoluensulfonyl chloride in anhydrous propanone will be dissolved in,
In dropping to above-mentioned solution, stirring reaction at 0-40 DEG C；After reaction terminates, suction filtration removes triethylamine hydrochloride precipitation；Filtrate is dense
It is added dropwise to after contracting in cooling absolute ether, separates out solid, absolute ethyl alcohol recrystallization obtains white solid mPEG-OTs；
MPEG-OTs is dissolved in DMF, the sodium salt or sylvite of amino acid is added, in stirring reaction at 40-90 DEG C；Reaction terminates
Afterwards, insoluble matter is filtered to remove, filtrate is added dropwise in cooling absolute ether under stirring, precipitation is collected by filtration, ether is cleaned,
Vacuum drying.
3. solid is dissolved in distilled water, pH to 3, CH is adjusted with hydrochloric acid2Cl2Extraction 3 times, combining extraction liquid, washing is anhydrous
Na2SO4It is dried overnight, solution decompression is steamed to 1/10th of original volume after filtering, is added drop-wise in cooling absolute ether, obtains white
Precipitation, vacuum drying, obtains white solid mPEG- amino acid derivativges；
MPEG- amino acid and oleanolic acid are dissolved in dry dichloromethane, are stirred in ice-water bath, add 4- dimethylamino pyrroles
Pyridine（DMAP）And N, N- dicyclohexylcarbodiimide（DCC）, room temperature reaction；Filter after completion of the reaction, wash organic phase, it is anhydrous
Na2SO4Dry, filtering, concentrate and precipitated with absolute ether, suction filtration, vacuum drying obtains target compound.
4. using amino acid as the application of the polyethylene glycol oleanolic acid derivate of linking arm, it is characterised in that the olive
The pharmaceutical composition of acid derivative has antitumor activity, for treating tumor disease.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109044978A (en) * | 2018-09-28 | 2018-12-21 | 佳木斯大学 | A kind of preparation method and applications of oleanolic acid nano particle |
| CN110548173A (en) * | 2019-08-26 | 2019-12-10 | 苏州恒瑞迦俐生生物医药科技有限公司 | preparation method of chemoembolization microsphere with microwave sensitization effect |
| CN112274688A (en) * | 2020-10-12 | 2021-01-29 | 南京江北新区生物医药公共服务平台有限公司 | Multi-layer composite dressing material with anti-inflammatory effect |
| CN112321819A (en) * | 2020-09-29 | 2021-02-05 | 南京江北新区生物医药公共服务平台有限公司 | Polyglutamic acid oleanolic acid derivative and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1493295A (en) * | 2003-09-06 | 2004-05-05 | 南昌弘益科技有限公司 | Oleanolic acid drip pill and its preparation method |
| CN1556828A (en) * | 2002-03-13 | 2004-12-22 | ƽ | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object |
| CN101928322A (en) * | 2010-03-02 | 2010-12-29 | 福州大学 | Ursolic acid modifier polyol monoesters with anti-cancer activity |
| CN102174191A (en) * | 2011-03-07 | 2011-09-07 | 天津科技大学 | Application of linker of polyethylene glycol and fat-soluble compounds in biological catalysis |
| CN102329362A (en) * | 2011-06-01 | 2012-01-25 | 福州大学 | Ursolic acid derivative chemically modified by polyethylene glycol and preparation method of ursolic acid derivative |
| CN102532246A (en) * | 2012-02-27 | 2012-07-04 | 浙江大学 | Oleanolic acid derivative as well as preparation method and application thereof |
| WO2016193309A1 (en) * | 2015-06-01 | 2016-12-08 | Dsm Ip Assets B.V. | New bis esters of ivy sapogenins for ruminants |
-
2016
- 2016-12-21 CN CN201611189746.7A patent/CN106750250B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1556828A (en) * | 2002-03-13 | 2004-12-22 | ƽ | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object |
| CN1243779C (en) * | 2002-03-13 | 2006-03-01 | 北京键凯科技有限公司 | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object |
| CN1493295A (en) * | 2003-09-06 | 2004-05-05 | 南昌弘益科技有限公司 | Oleanolic acid drip pill and its preparation method |
| CN101928322A (en) * | 2010-03-02 | 2010-12-29 | 福州大学 | Ursolic acid modifier polyol monoesters with anti-cancer activity |
| CN102174191A (en) * | 2011-03-07 | 2011-09-07 | 天津科技大学 | Application of linker of polyethylene glycol and fat-soluble compounds in biological catalysis |
| CN102329362A (en) * | 2011-06-01 | 2012-01-25 | 福州大学 | Ursolic acid derivative chemically modified by polyethylene glycol and preparation method of ursolic acid derivative |
| CN102532246A (en) * | 2012-02-27 | 2012-07-04 | 浙江大学 | Oleanolic acid derivative as well as preparation method and application thereof |
| WO2016193309A1 (en) * | 2015-06-01 | 2016-12-08 | Dsm Ip Assets B.V. | New bis esters of ivy sapogenins for ruminants |
Non-Patent Citations (1)
| Title |
|---|
| MARTA MEDINA-O"DONNELL ET AL.: "Semi-synthesis and antiproliferative evaluation of PEGylated pentacyclic triterpenes", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109044978A (en) * | 2018-09-28 | 2018-12-21 | 佳木斯大学 | A kind of preparation method and applications of oleanolic acid nano particle |
| CN109044978B (en) * | 2018-09-28 | 2020-12-29 | 佳木斯大学 | Preparation method and application of oleanolic acid nanoparticles |
| CN110548173A (en) * | 2019-08-26 | 2019-12-10 | 苏州恒瑞迦俐生生物医药科技有限公司 | preparation method of chemoembolization microsphere with microwave sensitization effect |
| CN112321819A (en) * | 2020-09-29 | 2021-02-05 | 南京江北新区生物医药公共服务平台有限公司 | Polyglutamic acid oleanolic acid derivative and preparation method thereof |
| CN112274688A (en) * | 2020-10-12 | 2021-01-29 | 南京江北新区生物医药公共服务平台有限公司 | Multi-layer composite dressing material with anti-inflammatory effect |
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